Abstract Increasing evidence suggests that protein tyrosine phosphatases cooperate with protein tyrosine kinases to promote tumorigenesis and thus are novel therapeutic targets. The Shp2 protein tyrosine phosphatase is activated by ErbB and other protein tyrosine kinases to regulate cell signaling. Recent studies of Shp2 in leukemias have established active Shp2 mutants as oncogenes. While Shp2 is overexpressed and often activated in carcinomas, the role of Shp2 in the tumorigenesis of carcinomas is less clear. The long-term goals of this project are to reveal signaling mechanisms and the role of Shp2 in carcinomas. Based on several lines of preliminary evidence, we postulate the central hypothesis that Shp2 is required for tumor growth of carcinomas. Specific Aim I will test the hypothesis that Shp2 is critical for tumor growth of carcinoma cells containing the wildtype K-Ras. A panel of carcinoma cell lines that contain inducible Shp2 shRNAs will be made to determine if Shp2 inhibition prevents tumor growth of these carcinoma cells. Tumor samples will be analyzed to identify major Shp2 binding proteins in the tumors. Shp2 contains several functional domains. The protein tyrosine phosphatase domain is being targeted for inhibitor development. Specific Aim II will evaluate if the Shp2 protein tyrosine phosphatase activity is essential for tumor growth of carcinoma cells. To gain mechanistic insights into the role of Shp2 in carcinomas, Shp2-regulated genes and proteins relevant to tumor growth will be identified. A Shp2- regulated signaling pathway is the Ras-MAP pathway, raising the question about whether K-Ras mutation could bypass the requirement of Shp2 in carcinomas. Because Shp2 regulates signaling events besides Ras and preliminary data suggest that Shp2 is not dispensable in carcinomas containing a mutant K-Ras, Specific Aim III will analyze if Shp2 inhibition is sufficient to impede tumorigenic activities and tumor growth of carcinomas cells harboring mutant K-Ras. Together, these experiments will greatly advance our knowledge about the role of Shp2 in tumorigenesis of carcinomas, give novel mechanistic insights into the function of Shp2 in carcinomas, and provide much needed data for the target evaluation of Shp2 as a novel class of therapeutic target in carcinomas. The project is relevant to the mission of National Cancer Institute.